Genetic Variant SIPA1L3:p.Ala63_Thr64dup (chr19-38081727-G-GGCCACC) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_015073.3(SIPA1L3):c.187_192dupGCCACC(p.Ala63_Thr64dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0063 in 1,602,804 control chromosomes in the GnomAD database, including 118 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0078 ( 22 hom., cov: 33)

Exomes 𝑓: 0.0061 ( 96 hom. )

Consequence

SIPA1L3
NM_015073.3 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.25

Variant links:

Genes affected

SIPA1L3 (HGNC:23801): (signal induced proliferation associated 1 like 3) This gene belongs to the signal induced proliferation associated 1 family of genes, which encode GTPase-activating proteins specific for the GTP-binding protein Rap1. Rap1 has been implicated in regulation of cell adhesion, cell polarity, and organization of the cytoskeleton. Like other members of the family, the protein encoded by this gene contains RapGAP and PDZ domains. In addition, this protein contains a C-terminal leucine zipper domain. This gene is proposed to function in epithelial cell morphogenesis and establishment or maintenance of polarity. Consistently, expression of the protein in cell culture showed localization to cell-cell borders in apical regions, and downregulation of the gene in 3D Caco2 cell culture resulted in abnormal cell polarity and morphogenesis. Allelic variants of this gene have been associated with congenital cataracts in humans. [provided by RefSeq, Feb 2016]

SIPA1L3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 19-38081727-G-GGCCACC is Benign according to our data. Variant chr19-38081727-G-GGCCACC is described in ClinVar as [Likely_benign]. Clinvar id is 782055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIPA1L3	NM_015073.3 link	c.187_192dupGCCACC	p.Ala63_Thr64dup	conservative_inframe_insertion	Exon 3 of 22	ENST00000222345.11	NP_055888.1	O60292B2RWP0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIPA1L3	ENST00000222345.11 link	c.187_192dupGCCACC	p.Ala63_Thr64dup	conservative_inframe_insertion	Exon 3 of 22	1	NM_015073.3	ENSP00000222345.4		O60292

Frequencies

GnomAD3 genomes

AF:

0.00788

AC:

1199

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0160

Gnomad ASJ

AF:

0.0291

Gnomad EAS

AF:

0.0650

Gnomad SAS

AF:

0.00621

Gnomad FIN

AF:

0.00443

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00500

Gnomad OTH

AF:

0.00955

GnomAD3 exomes

AF:

0.00937

AC:

2063

AN:

220134

Hom.:

AF XY:

0.00843

AC XY:

1028

AN XY:

121972

show subpopulations

Gnomad AFR exome

AF:

0.00100

Gnomad AMR exome

AF:

0.0141

Gnomad ASJ exome

AF:

0.0251

Gnomad EAS exome

AF:

0.0558

Gnomad SAS exome

AF:

0.00315

Gnomad FIN exome

AF:

0.00162

Gnomad NFE exome

AF:

0.00302

Gnomad OTH exome

AF:

0.0110

GnomAD4 exome

AF:

0.00614

AC:

8909

AN:

1450614

Hom.:

Cov.:

AF XY:

0.00600

AC XY:

4330

AN XY:

721318

show subpopulations

Gnomad4 AFR exome

AF:

0.00189

Gnomad4 AMR exome

AF:

0.0150

Gnomad4 ASJ exome

AF:

0.0272

Gnomad4 EAS exome

AF:

0.0440

Gnomad4 SAS exome

AF:

0.00408

Gnomad4 FIN exome

AF:

0.00282

Gnomad4 NFE exome

AF:

0.00406

Gnomad4 OTH exome

AF:

0.0106

GnomAD4 genome

AF:

0.00784

AC:

1193

AN:

152190

Hom.:

Cov.:

AF XY:

0.00808

AC XY:

601

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.00173

Gnomad4 AMR

AF:

0.0160

Gnomad4 ASJ

AF:

0.0291

Gnomad4 EAS

AF:

0.0646

Gnomad4 SAS

AF:

0.00580

Gnomad4 FIN

AF:

0.00443

Gnomad4 NFE

AF:

0.00500

Gnomad4 OTH

AF:

0.00992

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SIPA1L3: PM4, BS1, BS2 -

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 11, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29914532) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over